N,N-Dimethylacetamide Vaginal Self-nanoemulsifying Drug Delivery System for the Prevention or Preterm Birth

N,N-二甲基乙酰胺阴道自纳米乳化给药系统用于预防或早产

基本信息

批准号：
10620777
负责人：
Sandra Eve Reznik
金额：
$ 16.4万
依托单位：
ST. JOHN'S UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-11 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620777
关键词：
37 weeks gestation Acute Address Affect Atopobium vaginae Attenuated Birth Caproates Cells Cervix Uteri Clinical Clinical Trials Clinics and Hospitals Cognitive Collagen Communities Connective Tissue Country Creativeness Cytoplasm Data Dose Drug Delivery Systems Drug Formulations Excipients Extracellular Matrix FDA approved Family Fetus Formulation Funding Genetic Transcription Goals Health Personnel Health Professional Human Hydroxyprogesterone I Kappa B-Alpha Immune Impaired cognition Inflammation Inflammatory Inflammatory Response Investigation Knowledge Laboratories Leukocytes Life Longevity Macrophage Matrix Metalloproteinases Mediating Microscopic Modeling Molecular Morbidity - disease rate Mus N-Dimethylacetamide N NF-kappa B Neonatal Mortality Nuclear Translocation Pathologist Patients Perinatal Perinatal mortality demographics Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phenotype Placebos Population Population Heterogeneity Pre-Clinical Model Premature Birth Preparation Prevention Process Public Health Research Personnel Resources Risk Safety Signaling Molecule Societies Solvents Spontaneous abortion Structure Students Talents Teratogenic effects Teratogens Testing Tissues Toxic effect Training Translational Research Underserved Population United States Food and Drug Administration Uterus Vagina Work World Health Organization biomedical scientist care costs collagenase crosslink cytokine design drug development experience extracellular intraperitoneal mortality mouse model multicatalytic endopeptidase complex multidisciplinary nanoformulation neurobehavioral test nonhuman primate novel novel strategies p65 pre-clinical premature prevent pup research and development risk minimization skills small molecule systemic toxicity transcription factor trophoblast ubiquitin ligase

项目摘要

ABSTRACT Based on World Health Organization estimates, the annual rate of preterm birth (PTB) is greater than 10% in the majority of countries. Premature birth before 37 completed weeks of gestation is the leading cause of mortality in the first year of life and is associated with morbidity that has life-long cognitive consequences. Acute and lifespan care costs associated with preterm births have broad and sustained effects on families and are enormously expensive for society. Causes of PTB are multifactorial, but the single most common cause of PTB is inflammation. Sadly, there is currently no United States Food and Drug Administration approved drug for the prevention of PTB. One of the hurdles in translational research and drug development in this field is the risk of drug related toxicity affecting the fetus. Several years ago, we made the fortuitous discovery that the safe pharmaceutical solvent, N,N-dimethylacetamide (DMA), prevents PTB and rescues pups from spontaneous abortion in our mouse model. Further studies in our laboratory revealed that DMA suppresses nuclear translocation and activation of nuclear factor kappa B (NF-kB), a transcription factor that regulates immune cell-mediated inflammation. In addition, we have shown that DMA attenuates cytokine secretion from cultured human trophoblasts and from human placental explants. Recently, our laboratory has teamed up with our collaborator’s to develop a vaginal (pv) self-nanoemulsifying drug delivery system (SNEDDS), which takes advantage of the first uterine/cervix pass effect to deliver drugs introduced into the vaginal cavity directly to the cervix and uterus, thereby minimizing risk of systemic toxicity and teratogenicity. The specific aims of the current project are to 1) test the effects of our pv DMA SNEDDS on histomorphology and inflammatory responses in the cervix in a murine model; 2) determine the molecular mechanism whereby DMA inhibits NF-kB transcriptional activity; and 3) compare toxic and teratogenic effects of a DMA SNEDDS to intraperitoneal administration of DMA. To accomplish these aims, we assembled a team of experts in PTB, cervix histomorphology and drug formulation. This multidisciplinary team will be working alongside our students, who come from a diverse and underserved population. Although PTB is a global public health problem, rates of PTB are significantly higher among underserved populations. The novelty of re-purposing a readily available and inexpensive common drug excipient to prevent PTB, together with designing a vaginal formulation that can be administered by patients remote from clinics or hospitals, addresses a critical gap in the field of drug development for PTB.

抽象的根据世界卫生组织的估计，每年早产率（PTB）更大在大多数国家 /地区，超过10％。在37个完成的妊娠几周之前的早产是生命第一年死亡率的主要原因，与发病率有关终身后果。与早产相关的急性和寿命护理费用对家庭产生广泛和持续的影响，对社会来说非常昂贵。原因 PTB的多因素是多因素，但PTB的最常见原因是炎症。可悲的是目前尚无美国食品药品监督管理局批准的药物预防PTB。转化研究和药物开发的障碍之一场是影响胎儿的药物相关毒性的风险。几年前，我们做了偶然发现的是安全的药物溶液N，N-二甲基乙酰胺（DMA），可防止 PTB并在我们的小鼠模型中从发起堕胎中拯救了幼崽。在我们的进一步研究中实验室显示，DMA抑制了核因子的核易位和激活 Kappa B（NF-KB），一种调节免疫细胞介导的注射的转录因子。在此外，我们表明DMA减弱了培养的人的细胞因子分泌滋养细胞和人类的植物外植体。最近，我们的实验室与我们的合作者开发阴道（PV）自我乳化药物输送系统（SNEDDS），利用第一个子宫/子宫颈通行效应，将引入的药物传递到阴道腔直接到子宫颈和子宫，从而最大程度地减少了全身毒性的风险和致畸性。当前项目的具体目的是1）测试我们的PV DMA的影响鼠模型中子宫颈的组织形态和炎症反应的snedds； 2）确定DMA抑制NF-KB转录活性的分子机制； 3）比较DMA SNEDDS对腹膜内给药的有毒和致致造作用 DMA。为了实现这些目标，我们组建了一个专家团队PTB，子宫颈组织形态学和药物配方。这个多学科团队将与我们的学生一起工作尽管PTB是全球公共卫生问题，但在服务不足的人群中，PTB的率明显更高。重新点的新颖性一种易于使用且廉价的常见药物赋形剂，可预防PTB 设计一种阴道配方，可以由远离诊所或医院解决了PTB药物开发领域的关键差距。